CN110248931B - Salt of dioxygenase inhibitor and preparation method and application thereof - Google Patents
Salt of dioxygenase inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a salt of a dioxygenase inhibitor, a preparation method and application thereof, in particular to a salt of (Z) -N- (3-bromo-4-fluoro-phenyl) -4- ((2- (N- (cyclopropylsulfonyl) -S-methylsulfinimide) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-formamidine with a structure shown in a general formula (I), a preparation method and application thereof, and a pharmaceutical composition containing a therapeutically effective amount of the salt. The compound can be widely applied to treating or preventing cancers or tumors, virus infection, depression, neurodegenerative diseases, wounds, age-related cataract, organ transplant rejection or autoimmune diseases, and is expected to be developed into a new generation of immunosuppressants, wherein each substituent in the general formula (I) is defined as the same as the definition in the specification.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a salt of (Z) -N- (3-bromo-4-fluoro-phenyl) -4- ((2- (N- (cyclopropylsulfonyl) -S-methylsulfinimide) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine, a preparation method and application thereof.
Background
Tumors are one of the major diseases that seriously endanger human life, and more than half occur in developing countries. The incidence of malignant tumors in China generally tends to rise, the incidence is increased at a speed of 3% -5% per year, and 400 million people in China are expected to have cancer and 300 million people die of cancer by 2020, and the main reasons are that: aging, urbanization, industrialization and living habit change. In the drug market of Chinese hospitals, the sales scale of the antitumor drugs is steadily increased in recent years, the sales scale reaches 664.2 hundred million yuan in 2012 and is increased by 13.07 percent on a par, and the market scale of the antitumor drugs is estimated to reach 1055.7 hundred million yuan and is increased by 7.57 percent on a par by 2017.
Due to unlimited growth, infiltration and metastasis of malignant tumors, the three major clinical treatments (surgery, radiotherapy and chemotherapy) cannot completely remove or completely kill tumor cells, so that tumor metastasis or recurrence often occurs. The biological treatment of tumor is a new treatment method for preventing and treating tumor by applying modern biotechnology and related products, and is a fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy due to the characteristics of safety, effectiveness, low adverse reaction and the like, and the anti-tumor effect is obtained by mobilizing the natural defense mechanism of host (such as IDO-mediated tumor immune escape mechanism) or giving naturally-generated substances with strong targeting property.
Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a monomeric iron-containing heme protein consisting of 403 amino acid residues, including two folded alpha-helical domains, a large domain containing a catalytic pocket in which a substrate can interact with IDO in a hydrophobic manner. IDO is an enzyme catalyzing the conversion of tryptophan into formylkynurenine, is widely distributed in tissues of human and other mammals (rabbits and mice) except liver, is the only rate-limiting enzyme capable of catalyzing the catabolism of tryptophan except liver, and tryptophan is an amino acid necessary for cell maintenance, activation and proliferation and is also an essential component for constituting proteins. IDO is closely related to various cytokines such as Interferon (IFN), interleukin (IL), tumor necrosis factor and the like, and can activate IDO under certain conditions. On one hand, IDO causes local tryptophan depletion, so that T-cells are arrested in the middle stage of G1, and the proliferation of the T-cells is inhibited; on the other hand, the main product of canine urea produced by IDO catalysis of tryptophan metabolism induces T-cell apoptosis by oxygen free radical mediated changes in intracellular oxidants and antioxidants, which is an inherent immunosuppressive mechanism present in the body. A large number of studies at present show that IDO is highly expressed in leukemia cells, so that local T cell proliferation is inhibited, T-cell mediated immune reaction is inhibited, T-cell activation signal transduction is inhibited, and the attack of tumor cells escaping from an immune system is mediated. It has been found that most human tumors constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
PCT patent (application number: PCT/CN 2017/079585) discloses the structure of (Z) -N- (3-bromo-4-fluoro-phenyl) -4- ((2- (N- (cyclopropylsulfonyl) -S-methylsulfineimide) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-formamidine, and in subsequent development, the salt of the substance is comprehensively researched for the purposes of easy processing, filtration and drying of the product, suitable convenient storage, long-term stability of the product and the like, so that the most suitable salt form can be obtained.
Disclosure of Invention
The invention relates to a salt of a compound shown in a general formula (I), a stereoisomer thereof or a mixture form thereof,
wherein:
<xnotran> M , , , , , , 2,5- , 1- -2- , , , , , , ,4- , ,4- ,4- , , , , , , , , , , , , , , , , , , , , , -1,2- , , , , , , ,2- , , , , , , , , , , , ,1,5- , -2- , , , , , , , , ,4- , , , , , , , , L- ; </xnotran> And is provided with
y is an integer of 1,2 or 3.
A preferred embodiment of the invention is characterized in that the salt of the compound shown, its stereoisomers or mixtures thereof, is selected from the salts of the compounds of formula (II):
wherein: m and y are as defined for formula (I).
A preferred embodiment of the invention is characterized in that the salt of the compound shown, its stereoisomers or mixtures thereof, is selected from the salts of the compounds of formula (II-1):
wherein: m and y are as defined for formula (I).
A preferred embodiment of the invention is characterized in that said compound of formula (I), its stereoisomers or mixtures thereof, is characterized in that its free base crystalline form, is characterized by an XRPD with peaks at diffraction angles 2 θ (± 0.2 °) of 15.9, 17.2, 17.9, 19.7, 20.5, 21.1, 22.8, 27.0, 27.5, 28.1, 30.5, 33.6 and 35.5 ± 0.2 °, and by a melting peak at 176.4 ± 0.5 ℃ on DSC.
A preferred embodiment of the invention is characterized in that the compound of the general formula (I), the salts thereof, the stereoisomers thereof or the mixtures thereof, is selected from the group consisting of phosphoric acid, maleic acid, adipic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, fumaric acid and L-malic acid.
A preferred embodiment of the invention is characterized in that said compound of formula (I), in the form of a salt, a stereoisomer or a mixture thereof, is characterized in that M is selected from adipic acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid and fumaric acid; benzene sulfonic acid and p-methylbenzene sulfonic acid are preferred; more preferred is p-toluenesulfonic acid.
A preferred embodiment of the invention is characterized in that the compound of the general formula (I) is in the form of a salt, a stereoisomer or a mixture thereof, wherein y is 1.
A preferred embodiment of the invention is characterized in that said compound of formula (I), a salt thereof, a stereoisomer thereof or a mixture thereof, is characterized in that when M is p-toluenesulfonic acid, i.e. is p-toluenesulfonate, is characterized by XRPD showing peaks at diffraction angles 2 θ (± 0.2 °) of 6.1,9.6, 10.4, 14.8, 16.0, 17.1, 18.6, 19.4, 20.8, 22.1, 23.3, 24.6, 26.0 and 28.5 ± 0.2 °, in that it has a melting peak on DSC of 162.7 ± 0.5 ℃;
when M is benzenesulfonic acid, that is, a benzenesulfonate salt, characterized by XRPD showing peaks at diffraction angles 2 θ (± 0.2 °) of 5.2,6.1,7.6,9.5, 10.4, 10.4, 11.2, 14.1, 15.7, 16.0, 17.0, 18.2, 18.7, 19.4, 21.3, 22.2, 22.6, 23.0, 23.6, 24.5, 24.9, 26.1, 26.5, 26.9, 28.7, 29.3, 30.6, 33.3, 34.5, 35.6, 36.5 and 41.0 ± 0.2 °, the XRPD showing a peak at 152.3 ± 0.5 ℃ on DSC.
The invention also relates to a preparation scheme and a method for preparing the salt of the compound shown in the general formula (I), which comprises the following steps:
1) Preparation of stock solution: taking free alkali of a compound with a general formula, adding an organic solvent for dissolving to obtain a clear stock solution, wherein the concentration of the solution is as follows: 20-30 mg/mL; the organic solvent is preferably ethyl acetate, and the concentration of the solution is preferably 25mg/mL;
2) Preparation of a counter-ion acid solution: adding a counter-ion acid into an organic solvent to obtain a clarified counter-ion acid solution; the organic solvent is preferably ethanol, and the concentration is preferably 0.25-2 mol/L;
3) Preparation of compound salt: adding a counter ion acid solution into the stock solution to obtain a clear salt solution, naturally volatilizing, and drying in vacuum to obtain a salt of the compound shown in the general formula (I); the vacuum temperature is preferably 60 ℃, and the amount of the counter-ionic acid is preferably 1 to 1.2 equivalents;
wherein:
the organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, N-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane, tert-butyl alcohol or N, N-dimethylformamide; preferably ethyl acetate and ethanol;
<xnotran> , , , , , 2,5- , 1- -2- , , , , , , ,4- , ,4- ,4- , , , , , , , , , , , , , , , , , , , , , -1,2- , , , , , , ,2- , , , , , , , , , , , ,1,5- , -2- , , , , , , , , ,4- , , , , , , , , L- ; </xnotran> Preferably methanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; benzene sulfonic acid and p-methyl benzene sulfonic acid are most preferred.
The invention also relates to a preparation scheme and a method for preparing the salt of the compound shown in the general formula (I), which comprises the following steps:
1) Weighing a proper amount of free alkali, and dissolving the free alkali by using a benign solvent; the benign solvent is preferably ethyl acetate;
2) Weighing 1-3 equivalents of counter ion acid, and dissolving with an organic solvent; the organic solvent is preferably ethanol; the amount of the counter-ionic acid is preferably 1.2 equivalents;
3) Combining the two solutions, and dropwise adding a poor solvent until turbidity appears, or stirring overnight; poor solvents are preferably heptane and dichloromethane;
4) Standing or blow-drying to obtain the salt of the compound shown in the general formula (I);
wherein:
the benign solvent is selected from acetone, 2-butanone, tetrahydrofuran, 1, 4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate or acetonitrile; ethyl acetate, ethanol, 2-butanone, 1, 4-dioxane, and acetone are preferred.
The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, N-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane, tert-butyl alcohol or N, N-dimethylformamide; preferably ethyl acetate and ethanol; the benign solvent and the organic solution need to be mutually soluble when in use;
the poor solvent is selected from heptane, dichloromethane, water, methyl tert-butyl ether, toluene, isopropyl ether or ethanol; heptane and dichloromethane are preferred;
<xnotran> , , , , , 2,5- , 1- -2- , , , , , , ,4- , ,4- ,4- , , , , , , , , , , , , , , , , , , , , , -1,2- , , , , , , ,2- , , , , , , , , , , , ,1,5- , -2- , , , , , , , , ,4- , , , , , , , , L- ; </xnotran> Preferably methanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; benzene sulfonic acid and p-methyl benzene sulfonic acid are most preferred.
The invention also relates to a preparation scheme and the preparation method, wherein the solvent is ethyl acetate or ethanol.
The invention also relates to a preparation scheme and the preparation method, wherein the counter ion acid is benzene sulfonic acid and p-methyl benzene sulfonic acid.
A composition embodiment of the present invention, a pharmaceutical composition, comprises a therapeutically effective amount of said compound of formula (I), its salt, its stereoisomer or a mixture thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) is in the form of a salt, a stereoisomer, or a mixture thereof, or the composition is used for preparing a medicament for preventing and/or treating a disease having a pathological feature of an IDO-mediated tryptophan metabolic pathway.
A preferred embodiment of the present invention, said use, wherein said disease having pathological features of IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, alzheimer's disease, autoimmune diseases, depression, anxiety, cataract, psychological disorders and aids; the cancer is preferably selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid nephroma, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
The present invention also relates to a method for the treatment and/or prophylaxis of diseases which are characterized by pathologies of the IDO-mediated tryptophan metabolic pathway, which comprises administering to a patient a therapeutically effective dose of a compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. These diseases include infection by viruses such as AIDS, cell infections such as lyme disease and streptococcal infection, neurodegenerative disorders (e.g., alzheimer's disease, huntington's disease and parkinson's disease), autoimmune diseases, depression, anxiety, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), ocular disease states (e.g., cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
Another aspect of the present invention relates to a method of treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof. The method shows an outstanding therapeutic effect and less side effects, wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid nephroma, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer, preferably fallopian tube tumor, peritoneal tumor, stage IV melanoma, myeloma and breast cancer, more preferably breast cancer.
Drawings
FIG. 1 is a DSC-TGA (differential thermal-thermogravimetric analysis) representation of free base.
FIG. 2 is a DSC-TGA (differential thermal-thermogravimetric analysis) of phosphate.
FIG. 3 is a DSC-TGA (differential thermal-thermogravimetric analysis) graphical representation of the maleate salt.
FIG. 4 is a DSC-TGA (differential thermal-thermogravimetric analysis) profile of adipate.
FIG. 5 is a DSC-TGA (differential thermal-thermogravimetric analysis) graphic representation of benzenesulfonate salts.
FIG. 6 is a DSC-TGA (differential thermal-thermogravimetric analysis) graphic representation of p-toluenesulfonate.
FIG. 7 is a DSC-TGA (differential thermal-thermogravimetric analysis) profile of citrate salt.
FIG. 8 is a DSC-TGA (differential thermal-thermogravimetric analysis) graphic representation of malonate salts.
FIG. 9 is a DSC-TGA (differential thermal-thermogravimetric analysis) profile of L-malate.
Figure 10 is a DSC-TGA (differential thermal-thermogravimetric analysis) profile of the tartrate salt.
FIG. 11 is a DSC-TGA (differential thermal-thermogravimetric analysis) graphic representation of fumarate salt.
FIG. 12 is a graphical representation of the results of physical stability experiments for p-toluenesulfonic acid.
FIG. 13 is a graphical representation of the results of a physical stability experiment for benzenesulfonate salts.
FIG. 14 is a graphical representation of the results of a p-toluenesulfonate polycrystal screening experiment.
FIG. 15 is a graphical representation of the results of a benzene sulfonate polymorph screening experiment.
Detailed Description
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B and C.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
"thermogravimetric analysis (TGA)" refers to a thermogravimetric analysis (TGA) experiment.
"Differential Scanning Calorimetry (DSC)" refers to a Differential Scanning Calorimetry (DSC) experiment.
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
1.1 Experimental instruments
1.1.1 some parameters of the physicochemical measuring Instrument
1.2 conditions of liquid phase analysis
1.2.1 instruments and devices
| Name of the instrument | Type number |
| Analytical balance | Sartorius BSA224S-CW |
| Water purifier | Milli-Q Plus，Millipore |
| High performance liquid chromatograph | Agilent1260 |
| Pump | Agilent G1311B |
| Sample injector | G1329B |
| Column oven | G1316A |
| Detector | G1315D |
1.2.2 chromatographic conditions
A chromatographic column: waters X-Bridge (C18, 3.5 μm, 4.6X 100mm)
Flow rate: 1.0mL/min
Column temperature: 40 deg.C
Detection wavelength: 287nm
Sample introduction volume: 5 μ L
Operating time: 15min
Diluent agent: acetonitrile-water (v/v, 1: 1)
Mobile phase: a: water (0.1% trifluoroacetic acid);
b: acetonitrile (0.1% trifluoroacetic acid)
| T(min) | B(％) |
| 0 | 10 |
| 12 | 90 |
| 12.1 | 10 |
| 15 | 90 |
The first embodiment is as follows: natural volatilizing dry process for preparing
1.1 purpose of experiment:
different counter ion acids are selected, and a natural volatilizing method is adopted to detect which counter ion acids can form compound salts.
1.2 Experimental procedures:
1) Apparatus and device
| Name (R) | Type number | Source |
| Analytical balance | BSA224S-CW | Sartorius |
| Ultrasonic cleaning instrument | SK5200LHC | Shanghai department leads ultrasonic instrument |
| Liquid-transfering gun | Eppendorf(50mL，1000μL) | Eppendorf |
2) Operating procedure
(1) Preparation of stock solutions
288.8mg of free base of the compound of the general formula (VII) was added to 3X 3.85mL of ethyl acetate (using a 5mL pipette) and dissolved by sonication to give a clear solution of the following concentration: 25mg/mL.
(2) Salt solution preparation (counter ion acid addition 1.2 equivalents of free base)
And (3) adding the salt solution of the (2) into 1mL of stock solution (1), naturally volatilizing, and drying in vacuum at 60 ℃ to obtain the salt of the corresponding compound.
1.2.3 DSC-TGA test
FIG. 1: DSC-TGA (differential thermal-thermogravimetric analysis) profile of free base;
FIG. 2: DSC-TGA (differential thermal-thermogravimetric analysis) profile of phosphate;
FIG. 3: DSC-TGA (differential thermal-thermogravimetric analysis) profile of maleate;
FIG. 4: DSC-TGA (differential thermal-thermogravimetric analysis) profile of adipate;
FIG. 5 is a schematic view of: DSC-TGA (differential thermal-thermogravimetric analysis) profile of benzenesulfonate;
FIG. 6: DSC-TGA (differential thermal-thermogravimetric analysis) profile of p-toluenesulfonate;
FIG. 7 is a schematic view of: DSC-TGA (differential thermal-thermogravimetric analysis) profile of citrate;
FIG. 8: DSC-TGA (differential thermal-thermogravimetric analysis) profile of malonate;
FIG. 9: DSC-TGA (differential thermal-thermogravimetric analysis) profile of L-malate.
1.3 conclusion of the experiment
Analysis by DSC-TGA (differential thermal-thermogravimetric analysis) data, and comparison with data for the free base, indicates that all of the above counter-ionic acids are capable of forming compound salts.
The second embodiment: preparation by antisolvent method
2.1 purpose of experiment:
the benign solvent is selected to dissolve the compound and the compound is crystallized out using a poor solvent.
Benign solvent: acetone, 2-butanone (MEK), tetrahydrofuran (THF), 1, 4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile;
poor solvent: heptane, dichloromethane, water, methyl tert-butyl ether, toluene, isopropyl ether, ethanol; counter-ion acid: methanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, and L-malic acid.
2.2 Experimental procedures
1) Instrument and apparatus
| Name (R) | Model number | Source |
| Analytical balance | BSA224S-CW | Sartorius |
| Ultrasonic cleaning instrument | SK5200LHC | Shanghai department leads ultrasonic instrument |
| Circulating water pump | SHB-III | Zhengzhou great wall science and trade company Limited |
2) Operating procedure
The first scheme is as follows: selection of good solvent and anti-solvent for free base crystallization
(1) Benign solvents were: acetone, THF, 1, 4-dioxane, acetonitrile; anti-solvent: water;
(2) benign solvents were: acetone, THF, 1, 4-dioxane; anti-solvent: heptane, dichloromethane;
(3) benign solvents were: acetone, THF, 1, 4-dioxane, acetonitrile; anti-solvent: ethanol, isopropanol;
(4) benign solvents were: acetone, THF, 1, 4-dioxane, acetonitrile; anti-solvent: methyl tert-butyl ether, isopropyl ether;
the specific implementation method for selecting the free base antisolvent comprises the following steps:
weighing 50mg of free alkali, adding 2mL of benign solvent for dissolving, dropwise adding the anti-solvent under the stirring condition, stopping dropwise adding when white precipitate appears, standing, collecting the precipitate, performing vacuum drying, and detecting XRPD.
The screening of different benign and poor solvents is given in the following table:
from the above experiments, it can be seen that: the above-mentioned systems of benign solvents and poor solvents, ethanol, isopropanol, methyl tert-butyl ether, isopropyl ether are not ideal anti-solvents.
Scheme two is as follows: selection of good solvent and anti-solvent for compound salt crystallization
Benign solvents were: 2-butanone, 1, 4-dioxane, and ethyl acetate; the anti-solvent is: dichloromethane, n-heptane;
counter-ionic acid solution solvent: and (3) ethanol.
The specific implementation method for selecting the good solvent and the anti-solvent for preparing the salt comprises the following steps:
1) Weighing 150mg of free alkali, and dissolving the free alkali in 6mL of benign solvent;
2) Weighing 1.2 equivalents of counter ion acid, and dissolving with ethanol;
3) The free alkali solution and the counter ion acid solution are mutually soluble;
4) Dripping a poor solvent until turbidity appears, and stirring overnight;
5) Standing or blow-drying to obtain solid salt.
The solution formulation of free base and counter-ion acid is as follows:
the screening of different benign and poor solvents is given in the following table:
and #: the former represents the amount of anti-solvent added in terms of volume or weight, and the latter represents the phenomenon exhibited by the salt solution after addition of the anti-solvent in terms of volume or weight.
The above experiment shows that:
1) In a system in which the benign solvent is ethyl acetate and the anti-solvent is heptane, a large amount of solids are present in the phosphate, maleate, adipate, benzenesulfonate, p-toluenesulfonate, citrate, malonate, tartrate, fumarate and L-malate salts.
2) In a system with 1, 4-dioxane as benign solvent and dichloromethane as anti-solvent, adipic acid, maleic acid, citric acid and L-malic acid are slightly turbid, and the rest are clear solutions.
3) Black precipitates formed in hydrobromide, sulfate and nitrate salts.
XRPD ray diffraction data of free base with various salts
1. XRPD radiation diffraction data for adipate:
2. XRPD radiation diffraction data for D-tartrate:
3. XRPD radiation diffraction data for fumarate salt:
4. XRPD radiation diffraction data for p-toluenesulfonate salt:
5. XRPD radiation diffraction data for benzenesulfonate:
6. XRPD radiation diffraction data for free base:
example three: reaction molar ratio experiment of salt
3.1 purpose of experiment:
adding counter ions with different molar reaction ratios, and investigating the stability of the metering ratio of the generated p-toluenesulfonate to the benzenesulfonate under the given crystallization process conditions.
3.2 Experimental protocol:
the charged molar ratio of the counter ions is changed to be 0.6 to 2.2 (the molar ratio is the ratio of the number of moles of the counter ions to the number of moles of the free alkali), the feasibility of the salt crystallization process and the salt reaction stoichiometric ratio are examined by adopting the same crystallization process. And (3) measuring the mass percentage of the free alkali in the crystallized product by adopting an HPLC (high performance liquid chromatography) and external standard method, and comparing the mass percentage with the mass percentage of the theoretical reaction stoichiometric ratio.
3.3 Experimental results:
the counter ion amount of the fed materials is changed, so that solids can be crystallized; the amount of free base in the crystallized solid was quantified and the crystals precipitated were mostly free base and did not form salts in a 1: 1 molar ratio. When the molar ratio of the counter ion feeding amount is in the range of 1-1.2, the p-toluenesulfonic acid and the benzene sulfonate with the metering ratio of 1: 1 can be formed.
Example four: experiment for simulating solubility in artificial intestines and stomach
4.1 purpose of experiment:
and the solubility of different salts of the compound in simulated artificial gastrointestinal fluid is compared, so that a basis is provided for evaluation of the druggability of the salt.
4.2 Experimental protocol:
approximately 2mg of the compound was suspended in 1mL of artificial Simulated Gastric Fluid (SGF), fasted artificial simulated intestinal fluid (Fa), non-fasted artificial simulated intestinal fluid (Fe) and pure water for 16 hours, and the thermodynamic solubility of the compound at room temperature was determined by HPLC, external standard method.
4.3 Experimental results:
from the solubility results of the compound and the salt thereof in simulated intestinal fluid, the benzene sulfonate of the compound has a more obvious solubilizing effect compared with p-methyl benzene sulfonate, and is the salt which is selected firstly.
Example five: solid stability test
5.1 purpose of experiment:
and investigating the physical and chemical stability of the candidate compound salt under the acceleration condition or the influence factor condition, and providing a basis for salt screening and compound salt storage.
5.2 Experimental protocol:
1) P-toluenesulfonate salt:
taking 10mg of p-toluenesulfonate, sealing the p-toluenesulfonate, placing the p-toluenesulfonate in a 70 ℃ oven and a lighting box (5000 lx +/-500 lx), observing the p-toluenesulfonate for 5 days and 10 days under the conditions of opening the box at 40 ℃ and 75 percent of RH (saturated NaCl aqueous solution), 75 percent of RH (room temperature) and 65 percent of RH at 30 ℃ (saturated potassium chromate solution), measuring the content of salt by using HPLC (high performance liquid chromatography) and an external standard method, and calculating the change of substances related to the salt by using a chromatographic peak area normalization method.
2) Benzene sulfonate:
taking 10mg of benzenesulfonate, sealing in a 70 ℃ oven and a lighting box (5000 lx +/-500 lx), observing for 5 days and 10 days under the environment of 30 ℃ and RH75% (saturated NaCl aqueous solution) in an open environment, measuring the content of salt by using HPLC (high performance liquid chromatography) and an external standard method, and calculating the change of related substances of the salt by using a chromatographic peak area normalization method.
3) And (3) physical stability determination:
two salt samples for 10 days were examined and their XRPD determined and compared to the XRPD for 0 days.
5.3 Experimental results:
1) P-toluenesulfonate physicochemical stability results:
p-toluenesulfonate chemical stability results:
| sample name | Content% | Total impurities% | The impurities are increased% |
| P-toluenesulfonate-0 days | / | 0.44 | / |
| P-toluenesulfonate-50 deg.C&RH75% -5 days | 36.05 | 49.60 | 49.16 |
| P-toluenesulfonate-50 deg.C&RH75% -10 days | 20.48 | 67.87 | 67.43 |
| P-toluenesulfonate salt-70-5 days | 100.76 | 0.47 | 0.03 |
| P-methyl benzene sulfonate for-70-10 days | 103.21 | 0.50 | 0.06 |
| P-toluenesulfonate-light for-5 days | 97.97 | 1.84 | 1.40 |
| P-toluenesulfonate-light for-10 days | 95.62 | 2.75 | 2.31 |
| P-toluenesulfonate-30 deg.C&RH65% -5 days | 99.35 | 1.07 | 0.63 |
| P-toluenesulfonate-30 deg.C&RH65% -10 days | 94.08 | 2.09 | 1.65 |
| p-toluenesulfonate-RH 75% -5 days | 98.66 | 0.56 | 0.12 |
| p-toluenesulfonate-RH 75% -10 days | 97.80 | 0.66 | 0.22 |
The compound p-toluenesulfonate is extremely unstable under the conditions of 50 ℃ and RH75%, the impurities are increased by more than 40% after the compound is placed for 5 days, the related substances are increased by 0.63% after the compound is placed under the conditions of 30 ℃ and RH65% for 5 days, the related substances are not obviously increased after the compound is placed under the condition of RH75% for 5 days and 10 days, and the impurities are increased by 0.22% after the compound is placed under the condition of RH 75%; the compound p-toluenesulfonate is stable after being placed for 10 days at high temperature (70 ℃), and impurities are only increased by 0.06%; under the illumination condition, the compound p-toluenesulfonate is slightly degraded after being placed for 5 days and 10 days. Therefore, the compound p-toluenesulfonate should be packaged in a moisture-proof and light-proof manner.
Physical stability results for p-toluenesulfonic acid:
the test results are shown in FIG. 10
XRPD results show that when p-toluenesulfonate is examined for 10 days at 30 ℃ and RH65 percent and RH75 percent (room temperature) under the conditions of illumination and high temperature, the crystal form of the p-toluenesulfonate is not transformed compared with a 0-day sample.
1) Physical and chemical stability results of benzenesulfonate salt:
benzenesulfonate chemical stability results:
| sample name | Content% | Total impurities% | The impurities are increased% |
| Benzenesulfonate-0 day | / | 1.09 | / |
| Besylate-30 deg.C&RH65% -5 days | 96.19 | 1.03 | -0.06 |
| Besylate-30 deg.C&RH65% -10 days | 94.40 | 1.58 | 0.49 |
| Benzene sulfonate for-70-5 days | 99.67 | 0.96 | -0.13 |
| Benzene sulfonate for-70-10 days | 92.94 | 13.46 | 12.37 |
| Benzenesulfonate-light irradiation-5 days | 79.18 | / | / |
| Benzenesulfonate-light for-10 days | 77.18 | 22.88 | 21.79 |
Under the condition of 30 ℃ and RH65 percent, related substances are not obviously increased, but the content is obviously reduced; the compound benzene sulfonate is stable after being placed for 5 days under the condition of high temperature (70 ℃), and the impurity is suddenly increased by more than 12 percent after being placed for 10 days; under the illumination condition, the compound p-toluenesulfonate is greatly degraded after being placed for 5 days and 10 days.
Physical stability results for benzenesulfonate:
the test results are shown in fig. 11.
XRPD result shows that the crystal form of the compound benzenesulfonate is changed after being placed for 10 days under the condition of 30 ℃ and RH 65%; when the compound benzene sulfonate is inspected for 10 days under the conditions of illumination and high temperature, the crystal form of the compound benzene sulfonate is not transformed compared with a 0-day sample.
5.4 summarize: the results of the fixation stability of the compound p-toluenesulfonate and benzenesulfonate show that p-toluenesulfonate has more superiority than benzenesulfonic acid under the condition of meeting the moisture-proof and light-proof packaging conditions.
Example six: hygroscopicity test
6.1 purpose of the experiment
And the hygroscopicity of the compound under different relative humidity conditions is inspected, so that a basis is provided for screening and storing compound salts.
6.2 Experimental protocol:
and (3) placing the compound salt in saturated water vapor with different relative humidity to enable the compound and the water vapor to achieve dynamic balance, and calculating the percentage of moisture absorption weight gain of the compound after the balance.
6.3 Experimental results:
p-toluenesulfonate did not become hygroscopic under RH75% (chinese pharmacopoeia 2015 edition), benzenesulfonate was hygroscopic under RH 75%. And the p-toluenesulfonate is subjected to moisture absorption and desorption for four times under the condition of 0 to 95 percent relative humidity, and an XRPD mode is not changed, namely, no crystal form transformation exists; the benzene sulfonate can generate crystal transformation under the same processing condition.
From the viewpoint of hygroscopicity, p-toluenesulfonate is superior to benzenesulfonate.
Example seven: polycrystal screening experiment
7.1 purpose of the experiment: and finding out a relatively stable crystal form of the compound salt through polycrystal screening.
7.2 protocol: selecting organic solvent and water with certain solubility, suspending the compound in a solvent system, stirring and pulping at room temperature for 1 week, centrifuging, removing supernatant, vacuum drying the solid at 40 deg.C (-0.1 Mpa) overnight, measuring XRPD of the solid, and comparing with XRPD of compound salt.
7.3 Experimental results:
1) P-toluenesulfonate results:
the results of the polycrystal screening experiments are shown in FIG. 12.
The compound p-toluenesulfonate can be converted into free alkali by pulping in water, and the compound p-toluenesulfonate has stable crystal form and is not converted into other stable crystal forms by pulping in other solvents of EtOH, DCM, 88% acetone and ethyl acetate.
2) Besylate results:
the results of the polycrystal screening experiments are shown in FIG. 13.
The compound benzene sulfonate can be converted into free alkali in water and has crystal form conversion in other solvents except that the compound benzene sulfonate is pulped in ethyl acetate without crystal form conversion.
From the results of the polycrystal screening, p-toluenesulfonate was more stable in crystal form than benzenesulfonate.
Example eight: animal PK Studies
8.1 purpose of the experiment: the difference in exposure of compound salt to free base in animals was compared by animal PK studies.
8.2 protocol: the free base, p-toluenesulfonate and benzenesulfonate of the compounds were suspended homogeneously in an aqueous CMC-Na (0.5%) solution containing 0.1% of Tween80, and the mixture was gavaged and administered to rats in a dose of 100mg/kg for two rats in parallel, the amounts of the compounds being all converted to the same amount of free base.
8.3 Experimental results:
| free base | Benzenesulfonic acid salt | P-methylbenzenesulfonic acid salt | |
| T max (h) | 2 | 1 | 4 |
| C max (ng/mL) | 592.5 | 545.0 | 705.0 |
| AUC 0-t (ng/mL*h) | 2908.5 | 2419.1 | 4432.4 |
| AUC 0-∞ (ng/mL*h) | 3730.1 | 2584.5 | 5914.9 |
| t 1/2 (h) | 3.45 | 1.70 | 3.34 |
| MRT 0-∞ (h) | 5.53 | 3.49 | 6.11 |
The p-toluenesulfonate salt of the compound can obviously improve the exposure of the compound in rats.
Claims (21)
1. A salt of a compound of formula (I), a stereoisomer thereof or a mixture thereof,
wherein:
m is an inorganic or organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid, the organic acid is selected from the group consisting of 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy hydroxamic acid, adipic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, gluconic acid, glucuronic acid, glutamic acid, lactic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glutaric acid, 2-glutaratic acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, undecylenic acid, trifluoroacetic acid, p-toluenesulfonic acid, p-toluenesulfinic acid, L-toluenesulfonic acid, and L-benzenesulfenic acid; and is
y is an integer of 1,2 or 3.
2. The salt of the compound of formula (I), its stereoisomers or mixtures thereof according to claim 1, selected from the salts of compounds of formula (II):
wherein:
m and y are as defined for formula (I).
3. A compound of formula (I) according to claim 1 or 2, in free base crystalline form, characterized by an XRPD exhibiting peaks at diffraction angles 2 Θ (± 0.2 °) of 15.9, 17.2, 17.9, 19.7, 20.5, 21.1, 22.8, 27.0, 27.5, 28.1, 30.5, 33.6 and 35.5 ± 0.2 °, with a melting peak at 176.4 ± 0.5 ℃ on DSC.
4. The salt of the compound of formula (I), its stereoisomers or mixtures thereof, according to claim 1 or 2, wherein M is selected from phosphoric acid, maleic acid, adipic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, malonic acid, tartaric acid, fumaric acid and L-malic acid.
5. The salt of the compound of formula (I), its stereoisomers or mixtures thereof, according to any of claims 1-2, wherein M is selected from adipic acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid and fumaric acid.
6. The salt of the compound of formula (I), its stereoisomers or mixtures thereof according to claim 5, wherein M is selected from the group consisting of benzenesulfonic acid and p-toluenesulfonic acid.
7. The compound of formula (I), its salts, its stereoisomers or mixtures thereof according to claim 5, wherein M is selected from p-toluenesulfonic acid.
8. The salt of the compound of formula (I), its stereoisomers or mixtures thereof, according to any of claims 1-2, wherein y is 1.
9. A compound according to any one of claims 1-2 of the general formula (I):
when M is p-toluenesulfonic acid, i.e., is a p-toluenesulfonic acid salt, characterized by an XRPD having peaks at diffraction angles 2 θ (± 0.2 °) of 6.1,9.6, 10.4, 14.8, 16.0, 17.1, 18.6, 19.4, 20.8, 22.1, 23.3, 24.6, 26.0 and 28.5 ± 0.2 °, having a melting peak on DSC of 162.7 ± 0.5 ℃;
when M is benzenesulfonic acid, that is, a benzenesulfonate salt, it is characterized by having an XRPD showing peaks at diffraction angles 2 θ (± 0.2 °) of 5.2,6.1,7.6,9.5, 10.4, 10.4, 11.2, 14.1, 15.7, 16.0, 17.0, 18.2, 18.7, 19.4, 21.3, 22.2, 22.6, 23.0, 23.6, 24.5, 24.9, 26.1, 26.5, 26.9, 28.7, 29.3, 30.6, 33.3, 34.5, 35.6, 36.5 and 41.0 ± 0.2 °, and by having a melting peak at 152.3 ± 0.5 ℃ on DSC.
10. A process for the preparation of a salt of a compound of formula (I) according to any one of claims 1 to 2,4 to 8, comprising the steps of:
1) Preparation of stock solution: taking free alkali of a compound with a general formula, adding an organic solvent for dissolving to obtain a clear stock solution, wherein the concentration of the solution is as follows: 20-30 mg/mL;
2) Preparation of a counter-ion acid solution: adding a counter-ion acid into an organic solvent to obtain a clarified counter-ion acid solution;
3) Preparation of compound salt: adding a counter ion acid solution into the stock solution to obtain a clear salt solution, naturally volatilizing, and drying in vacuum to obtain a salt of the compound shown in the general formula (I);
wherein:
the organic solvent is selected from methanol, ethanol, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, 2-butanone, 3-pentanone, 1, 4-dioxane or tert-butyl alcohol;
the counter ion acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, the organic acid is selected from the group consisting of 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy acid, adipic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, gluconic acid, glucuronic acid, glutamic acid, lactic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thionic acid, undecylenic acid, trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and L-toluenesulfonic acid.
11. The method of claim 10, wherein the counter-ionic acid is selected from methanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, and L-malic acid.
12. The method according to claim 10, wherein the organic solvent used in the preparation of the stock solution is selected from ethyl acetate, and the concentration of the solution is 25mg/mL;
the organic solvent in the preparation of the counter ion acid solution is selected from ethanol, and the concentration is 0.25-2 mol/L;
the vacuum temperature in the preparation of the compound salt is selected from 60 ℃, and the amount of the counter ion acid is selected from 1 to 1.2 equivalents.
13. A process for the preparation of a salt of a compound of formula (I) according to any one of claims 1 to 2,4 to 9, comprising the steps of:
1) Weighing a proper amount of free alkali, and dissolving the free alkali by using a benign solvent;
2) Weighing 1-3 equivalents of counter ion acid, and dissolving with an organic solvent;
3) Combining the two solutions, and dropwise adding a poor solvent until turbidity appears, or stirring overnight;
4) Standing or blow-drying to obtain the salt of the compound shown in the general formula (I);
wherein:
the benign solvent is selected from acetone, 2-butanone, tetrahydrofuran, 1, 4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate or acetonitrile;
the organic solvent is selected from methanol, ethanol, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, 2-butanone, 3-pentanone, 1, 4-dioxane or tert-butyl alcohol; the benign solvent and the organic solution need to be mutually soluble when in use;
the poor solvent is selected from heptane, dichloromethane, methyl tert-butyl ether, toluene or isopropyl ether
The counter ion acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, the organic acid is selected from the group consisting of 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy hydroxamic acid, adipic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, gluconic acid, glucuronic acid, glutamic acid, lactic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glutaric acid, 2-glutaratic acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, undecylenic acid, trifluoroacetic acid, p-toluenesulfonic acid, L-toluenesulphonic acid, and L-toluenesulfonic acid.
14. The method for producing according to claim 13, wherein the benign solvent is selected from the group consisting of ethyl acetate, ethanol, 2-butanone, 1, 4-dioxane and acetone;
the organic solvent is selected from ethyl acetate and ethanol;
the poor solvent is selected from heptane and dichloromethane;
the counter ion acid is selected from methanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid.
15. The production method according to claim 13, wherein the benign solvent is selected from ethyl acetate; the organic solvent is selected from ethanol; the amount of the counter-ionic acid is selected from 1.2 equivalents; the poor solvent is selected from heptane and dichloromethane.
16. The method according to claim 10, wherein the organic solvent is ethyl acetate or ethanol.
17. The method according to claim 10 or 13, wherein the counter-ionic acid is benzenesulfonic acid or p-toluenesulfonic acid.
18. A pharmaceutical composition comprising a therapeutically effective amount of a salt of a compound of general formula (I), its stereoisomers or a mixture thereof, according to any one of claims 1-2,4-9, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
19. Use of a compound of general formula (I), as a salt thereof, a stereoisomer thereof or a mixture thereof, according to any one of claims 1 to 2,4 to 9, or a composition according to claim 18, for the preparation of a medicament for the prevention and/or treatment of diseases having pathological features of the IDO-mediated tryptophan metabolic pathway.
20. The use according to claim 19, wherein the disease having pathological features of IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, alzheimer's disease, autoimmune diseases, cataracts, psychological disorders and aids; the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastomas, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma and myeloma.
21. The use according to claim 20, wherein the disease having pathological features of an IDO mediated tryptophan metabolic pathway is selected from the group consisting of cancer, depression, anxiety; the cancer is selected from non-small cell lung cancer.
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| CN102164902A (en) * | 2008-07-08 | 2011-08-24 | 因塞特公司 | 1,2, 5-oxadiazole as an inhibitor of indoleamine 2, 3-dioxygenase |
| CN105481789A (en) * | 2014-09-15 | 2016-04-13 | 中国科学院上海有机化学研究所 | Indoleamine-2, 3-dioxygenase inhibitor and preparation method thereof |
| WO2016155545A1 (en) * | 2015-03-31 | 2016-10-06 | 江苏恒瑞医药股份有限公司 | Sulfamyl-containing 1,2,5-oxadiazole derivative, preparation method therefor and use thereof in pharmaceuticals |
| CN107304191A (en) * | 2016-04-20 | 2017-10-31 | 上海翰森生物医药科技有限公司 | Indoleamine 2,3 dioxygenase inhibitors and preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102164902A (en) * | 2008-07-08 | 2011-08-24 | 因塞特公司 | 1,2, 5-oxadiazole as an inhibitor of indoleamine 2, 3-dioxygenase |
| CN105481789A (en) * | 2014-09-15 | 2016-04-13 | 中国科学院上海有机化学研究所 | Indoleamine-2, 3-dioxygenase inhibitor and preparation method thereof |
| WO2016155545A1 (en) * | 2015-03-31 | 2016-10-06 | 江苏恒瑞医药股份有限公司 | Sulfamyl-containing 1,2,5-oxadiazole derivative, preparation method therefor and use thereof in pharmaceuticals |
| CN107304191A (en) * | 2016-04-20 | 2017-10-31 | 上海翰森生物医药科技有限公司 | Indoleamine 2,3 dioxygenase inhibitors and preparation method and application |
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